Herbal products have gained popularity for their use in the treatment of diseases in humans. Although the clinical effect of most herbal products is unknown, many herbs contain derivatives with biological activity. One such herb is licorice root. Extracts of licorice root have been shown to have biological activity that includes antioxidant activity (Palagina, M. V. et al. 1999. Ter. Arkh. 71:45-48), inhibition of melanin synthesis (Yokota, T. et al. 1998. Pigment Cell Res. 11:355-361), inhibition of angiogenesis (Kobayashi, S. et al. 1995. Biol. Phar,. Bull. 18:1382-1386), anti-microbial activity (Mitscher, L. A. et al. 1980. J. Nat. Prod. 43: 259-269), anti-parasitic activity (Zhai, L. et al. 1995. Antimicrob. Agents Chemotherap. 39:2742-2748), and anti-tumor activity (Shibata, S. 1994. Stem Cells 12:44-52). Several compounds responsible for the various biological effects have been isolated. Examples of such compounds include glabridin (Yokota, T. et al. 1998. Pigment Cell Res. 11:355-361), isoliquiritin (Kobayashi, S. et al. 1995. Biol. Pharm. Bull. 18:1382-1386), glycyrrhizin (Raggi, M. A. et al. 1995. Boll. Chim. Farm. 134:634-638), and licochalcone A, a non-hydroxylated chalcone compound (Shibata, S. 1994. Stem Cells 12:44-52).
Recent studies with a combination of eight herbs, that included licorice root, called PC-SPES, has been shown to have potent clinical and biological activity (DiPaola, R. S. et al. 1998. N. Engl. J. Med. 339:785-791). PC-SPES showed anti-prostate cancer activity which was attributable to phytoestrogens that produced a chemical castration. Another study demonstrated that licorice root alone was capable of decreasing circulating testosterone levels in men (Armanini, D. et al. 1999. N. Engl. J. Med. 341:1158). Additional studies in patients have demonstrated PC-SPES to have anti-tumor activity refractory to chemical castration, thus indicating that other mechanisms may be responsible for the anti-tumorigenic activity of this licorice root-herbal combination therapy (Small, E. et al. 1999. N. Engl. J. Med. 340(7):785-791).
PC-SPES extracts have also been shown to induce apoptosis in tumor cell lines and decreased the expression of bcl-2. Bcl-2 is a 26 kDa protein that blocks cell death by inhibiting cytochrome c release from mitochondria, a critical event in the apoptotic pathway. Overexpression of bcl-2 protects cells from death promoting stimuli, whereas lowering bcl-2 levels increases cell death and sensitivity to chemotherapy (Reed, J. C. 1997. Nature 387:773-776). Recent studies suggest that drugs which decrease bcl-2 expression, or inactivate the molecule through phosphorylation, induce apoptosis. For example, paclitaxel, docetaxol, vincristine, and vinblastine alter microtubule structure and induce apoptosis in association with bcl-2 phosphorylation (Hadlar, S. et al. 1996. Cancer Res. 56:1253; Haldar, S. et al. 1995. Proc. Natl. Acad. Sci. USA 92:4507-4511).
It has now been found that compounds extracted from licorice root, in particular hydroxylated chalcones, have activity consistent with induction of apoptosis and potential activity as anti-tumorigenic and anti-carcinogenic agents.
An object of the present invention is to provide a hydroxylated chalcone compound extracted and purified from Glycyrrhiza glabra. In a preferred embodiment the compound comprises 1-propanone-1-(2,4-dihydroxyphenyl)-3-hydroxy-3-(4-hydroxyphenyl).
Another object of the present invention is to provide a method of inducing phosphorylation of bcl-2 comprising contacting cells or tissues with a hydroxylated chalcone compound.
Yet another object of the present invention is to provide a method of inducing apoptosis in cells or tissues comprising contacting cells or tissues with a hydroxylated chalcone compound.
Also included in the present invention are methods for inhibiting tumor cell growth and preventing and treating cancer via contacting tumor cells or tissues with an effective amount of a hydroxylated chalcone compound.